A treatment for cocaine addiction remains elusive due to incomplete knowledge of the circuitry controlling the overwhelming desire to relapse to drug use. Using the cue-induced reinstatement rodent model of relapse, synaptic changes that are necessary for reinstating cocaine seeking have been discovered in the circuit containing glutamatergic inputs to the core of the nucleus accumbens (NAcore) and GABAergic inputs from the NAcore to the dorsolateral ventral pallidum (dlVP). The overarching hypothesis of this renewal application continues to be that relapse depends on synaptic plasticity produced by cocaine use at excitatory synapses in NAcore and GABAergic synapses in dlVP. A critical gap in our understanding is the relative roles played by the two distinct classes of NAcore D1- and D2-expressing medium spiny neurons (MSNs). The development of transgenic D1 and D2 Cre mice and optogenetic strategies provides the necessary technology to determine how these MSN populations regulate relapse. Our preliminary data show that the classic direct and indirect basal ganglia circuits do not apply to NAcore D1 MSNs, in that the indirect projection to dlVP contains substantial inputs from both D1 and D2 MSNs. In Aim 1 we will characterize this aberration from classical dogma, and determine if any specificity exists regarding D1 and D2 synapses on dlVP neurons projecting to distinct subcortical target regions. We will also determine which D1/D2 cell group and dlVP efferent is necessary for reinstated cocaine seeking. Aim 2 focuses on discoveries that cued reinstatement produces transient potentiation at glutamatergic synapses on NAcore MSNs that is necessary for cue-induced reinstatement, and will determine which glutamatergic afferent and which MSN cell type (D1 or D2) harbors the molecular, morphological and electrophysiological markers of reinstatement-induced synaptic potentiation. Aim 3 focuses on how neuropeptides co- localized in D1 vs D2 MSNs regulate GABA synapses in dlVP and how cocaine changes this regulation in a manner necessary for cues to reinstate cocaine seeking. Together, these experiments will provide a comprehensive understanding of the circuitry and synaptic plasticity mediating cue-induced relapse to cocaine seeking.